title: Synthetic studies of centromere-associated protein-E (CENP-E) inhibitors: 1.Exploration of fused bicyclic core scaffolds using electrostatic potential map.
abstract: Centromere-associated protein-E (CENP-E), a mitotic kinesin that plays an important role in mitotic progression, is an attractive target for cancer therapeutic drugs. For the purpose of developing novel CENP-E inhibitors as cancer therapeutics, we investigated a fused bicyclic compound identified by high throughput screening, 4-oxo-4,5-dihydrothieno[3,4-c]pyridine-6-carboxamide 1a. Based on this scaffold, we designed inhibitors for efficient binding at the L5 site in CENP-E utilizing homology modeling as well as electrostatic potential map (EPM) analysis to enhance CENP-E inhibitory activity. This resulted in a new lead, 5-bromoimidazo[1,2-a]pyridine 7, which showed potent CENP-E enzyme inhibition (IC50: 50nM) and cellular activity with accumulation of phosphorylated histone H3 in HeLa cells. Our homology model and EPM analysis proved to be useful tools for the rational design of CENP-E inhibitors.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. takaharu.hirayama@takeda.com
authors.forename: Takaharu
authors.initials: T
authors.lastname: Hirayama
authors.forename: Masanori
authors.initials: M
authors.lastname: Okaniwa
authors.forename: Takashi
authors.initials: T
authors.lastname: Imada
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ohashi
authors.forename: Momoko
authors.initials: M
authors.lastname: Ohori
authors.forename: Kenichi
authors.initials: K
authors.lastname: Iwai
authors.forename: Kouji
authors.initials: K
authors.lastname: Mori
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kawamoto
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yokota
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Tanaka
authors.forename: Tomoyasu
authors.initials: T
authors.lastname: Ishikawa
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D001643:Bridged Bicyclo Compounds / Q000737:chemistry*; D002868:Chromosomal Proteins, Non-Histone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D055672:Static Electricity; D013329:Structure-Activity Relationship
chemical_list: C586764:5-bromoimidazo(1,2-a)pyridine; D000577:Amides; D001643:Bridged Bicyclo Compounds; D002868:Chromosomal Proteins, Non-Histone; D006657:Histones; D007093:Imidazoles; D011725:Pyridines; C068688:centromere protein E
keywords: (1)H NMR; 4-Oxo-4,5-dihydrothieno[3,4-c]pyridine-6-carboxamide; CENP-E; DSC; EPM; Electrostatic potential map (EPM); Imidazo[1,2-a]pyridine; PD; SAR; ZATPRXWLTXOXAQ-UHFFFAOYSA-N; centromere-associated protein-E; differential scanning calorimetry; electrostatic potential map; pharmacodynamic; proton nuclear magnetic resonance; structure–activity relationship